Loss of host type-I IFN signaling accelerates metastasis and impairs NK-cell antitumor function in multiple models of breast cancer

Jai Rautela, Nikola Baschuk, Clare Y Slaney, Krishnath M Jayatilleke, Kun Xiao, Bradley N Bidwell, Erin C Lucas, Edwin Hawkins, Peter Lock, Christina S F Wong, Weisan Chen, Robin L Anderson, Paul John Hertzog, Daniel Mark Andrews, Andreas Moller, Belinda S Parker

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Abstract

Metastatic progression is the major cause of breast cancer related mortality. By examining multiple syngeneic preclinical breast cancer models in mice lacking a functional type-I interferon receptor (Ifnar1-/- mice), we show that host-derived type-I interferon (IFN) signaling is a critical determinant of metastatic spread that is independent of primary tumor growth. In particular, we show that bone metastasis can be accelerated in Balb/c Ifnar1-/- mice bearing either 4T1 or 66cl4 orthotopic tumors and, for the first time, present data showing the development of bone metastasis in the C57Bl/6 spontaneous MMTV-PyMT-driven model of tumorigenesis. Further exploration of these results revealed that endogenous type-I IFN signaling to the host haematopoietic system is a key determinant of metastasis-free survival and critical to the responsiveness of the circulating NK cell population. We find that in vivo stimulated NK cells derived from WT, but not Ifnar1-/- mice can eliminate the 4T1 and 66cl4 breast tumor lines with varying kinetics in vitro. Together, this study indicates that the dysregulated immunity resulting from a loss of host type-I IFN signaling is sufficient to drive metastasis, and provides a rationale for targeting the endogenous type-I IFN pathway as an anti-metastatic strategy.
Original languageEnglish
Pages (from-to)1207 - 1217
Number of pages11
JournalCancer Immunology Research
Volume3
Issue number11
DOIs
Publication statusPublished - 2015

Cite this

Rautela, Jai ; Baschuk, Nikola ; Slaney, Clare Y ; Jayatilleke, Krishnath M ; Xiao, Kun ; Bidwell, Bradley N ; Lucas, Erin C ; Hawkins, Edwin ; Lock, Peter ; Wong, Christina S F ; Chen, Weisan ; Anderson, Robin L ; Hertzog, Paul John ; Andrews, Daniel Mark ; Moller, Andreas ; Parker, Belinda S. / Loss of host type-I IFN signaling accelerates metastasis and impairs NK-cell antitumor function in multiple models of breast cancer. In: Cancer Immunology Research. 2015 ; Vol. 3, No. 11. pp. 1207 - 1217.
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title = "Loss of host type-I IFN signaling accelerates metastasis and impairs NK-cell antitumor function in multiple models of breast cancer",
abstract = "Metastatic progression is the major cause of breast cancer related mortality. By examining multiple syngeneic preclinical breast cancer models in mice lacking a functional type-I interferon receptor (Ifnar1-/- mice), we show that host-derived type-I interferon (IFN) signaling is a critical determinant of metastatic spread that is independent of primary tumor growth. In particular, we show that bone metastasis can be accelerated in Balb/c Ifnar1-/- mice bearing either 4T1 or 66cl4 orthotopic tumors and, for the first time, present data showing the development of bone metastasis in the C57Bl/6 spontaneous MMTV-PyMT-driven model of tumorigenesis. Further exploration of these results revealed that endogenous type-I IFN signaling to the host haematopoietic system is a key determinant of metastasis-free survival and critical to the responsiveness of the circulating NK cell population. We find that in vivo stimulated NK cells derived from WT, but not Ifnar1-/- mice can eliminate the 4T1 and 66cl4 breast tumor lines with varying kinetics in vitro. Together, this study indicates that the dysregulated immunity resulting from a loss of host type-I IFN signaling is sufficient to drive metastasis, and provides a rationale for targeting the endogenous type-I IFN pathway as an anti-metastatic strategy.",
author = "Jai Rautela and Nikola Baschuk and Slaney, {Clare Y} and Jayatilleke, {Krishnath M} and Kun Xiao and Bidwell, {Bradley N} and Lucas, {Erin C} and Edwin Hawkins and Peter Lock and Wong, {Christina S F} and Weisan Chen and Anderson, {Robin L} and Hertzog, {Paul John} and Andrews, {Daniel Mark} and Andreas Moller and Parker, {Belinda S}",
year = "2015",
doi = "10.1158/2326-6066.CIR-15-0065",
language = "English",
volume = "3",
pages = "1207 -- 1217",
journal = "Cancer Immunology Research",
issn = "2326-6066",
publisher = "American Association for Cancer Research (AACR)",
number = "11",

}

Rautela, J, Baschuk, N, Slaney, CY, Jayatilleke, KM, Xiao, K, Bidwell, BN, Lucas, EC, Hawkins, E, Lock, P, Wong, CSF, Chen, W, Anderson, RL, Hertzog, PJ, Andrews, DM, Moller, A & Parker, BS 2015, 'Loss of host type-I IFN signaling accelerates metastasis and impairs NK-cell antitumor function in multiple models of breast cancer', Cancer Immunology Research, vol. 3, no. 11, pp. 1207 - 1217. https://doi.org/10.1158/2326-6066.CIR-15-0065

Loss of host type-I IFN signaling accelerates metastasis and impairs NK-cell antitumor function in multiple models of breast cancer. / Rautela, Jai; Baschuk, Nikola; Slaney, Clare Y; Jayatilleke, Krishnath M; Xiao, Kun; Bidwell, Bradley N; Lucas, Erin C; Hawkins, Edwin; Lock, Peter; Wong, Christina S F; Chen, Weisan; Anderson, Robin L; Hertzog, Paul John; Andrews, Daniel Mark; Moller, Andreas; Parker, Belinda S.

In: Cancer Immunology Research, Vol. 3, No. 11, 2015, p. 1207 - 1217.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Loss of host type-I IFN signaling accelerates metastasis and impairs NK-cell antitumor function in multiple models of breast cancer

AU - Rautela, Jai

AU - Baschuk, Nikola

AU - Slaney, Clare Y

AU - Jayatilleke, Krishnath M

AU - Xiao, Kun

AU - Bidwell, Bradley N

AU - Lucas, Erin C

AU - Hawkins, Edwin

AU - Lock, Peter

AU - Wong, Christina S F

AU - Chen, Weisan

AU - Anderson, Robin L

AU - Hertzog, Paul John

AU - Andrews, Daniel Mark

AU - Moller, Andreas

AU - Parker, Belinda S

PY - 2015

Y1 - 2015

N2 - Metastatic progression is the major cause of breast cancer related mortality. By examining multiple syngeneic preclinical breast cancer models in mice lacking a functional type-I interferon receptor (Ifnar1-/- mice), we show that host-derived type-I interferon (IFN) signaling is a critical determinant of metastatic spread that is independent of primary tumor growth. In particular, we show that bone metastasis can be accelerated in Balb/c Ifnar1-/- mice bearing either 4T1 or 66cl4 orthotopic tumors and, for the first time, present data showing the development of bone metastasis in the C57Bl/6 spontaneous MMTV-PyMT-driven model of tumorigenesis. Further exploration of these results revealed that endogenous type-I IFN signaling to the host haematopoietic system is a key determinant of metastasis-free survival and critical to the responsiveness of the circulating NK cell population. We find that in vivo stimulated NK cells derived from WT, but not Ifnar1-/- mice can eliminate the 4T1 and 66cl4 breast tumor lines with varying kinetics in vitro. Together, this study indicates that the dysregulated immunity resulting from a loss of host type-I IFN signaling is sufficient to drive metastasis, and provides a rationale for targeting the endogenous type-I IFN pathway as an anti-metastatic strategy.

AB - Metastatic progression is the major cause of breast cancer related mortality. By examining multiple syngeneic preclinical breast cancer models in mice lacking a functional type-I interferon receptor (Ifnar1-/- mice), we show that host-derived type-I interferon (IFN) signaling is a critical determinant of metastatic spread that is independent of primary tumor growth. In particular, we show that bone metastasis can be accelerated in Balb/c Ifnar1-/- mice bearing either 4T1 or 66cl4 orthotopic tumors and, for the first time, present data showing the development of bone metastasis in the C57Bl/6 spontaneous MMTV-PyMT-driven model of tumorigenesis. Further exploration of these results revealed that endogenous type-I IFN signaling to the host haematopoietic system is a key determinant of metastasis-free survival and critical to the responsiveness of the circulating NK cell population. We find that in vivo stimulated NK cells derived from WT, but not Ifnar1-/- mice can eliminate the 4T1 and 66cl4 breast tumor lines with varying kinetics in vitro. Together, this study indicates that the dysregulated immunity resulting from a loss of host type-I IFN signaling is sufficient to drive metastasis, and provides a rationale for targeting the endogenous type-I IFN pathway as an anti-metastatic strategy.

UR - http://www.ncbi.nlm.nih.gov/pubmed/26198985

U2 - 10.1158/2326-6066.CIR-15-0065

DO - 10.1158/2326-6066.CIR-15-0065

M3 - Article

VL - 3

SP - 1207

EP - 1217

JO - Cancer Immunology Research

JF - Cancer Immunology Research

SN - 2326-6066

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